There has been a drive towards reducing the size of instrumentation used for analyzing and otherwise manipulating fluid samples such as biological fluid samples. The reduced size offers several advantages, including the ability to analyze very small samples, increased analytical speed, the ability to use reduced amounts of reagents, and reduced overall cost.
Various devices for microfluid applications have been proposed. These devices typically include a glass or silicon substrate having a lithographically patterned and etched surface provided with one or more structures forming a microfluid processing architecture. Plastic substrates such as polyimides, polyesters, and polycarbonates have been proposed as well.
There is a need for polymer-based microfluidic articles that can be produced efficiently in commercial-scale quantities, e.g., in the form of a roll good, and that can be selectively tailored to perform a variety of functions, including analytical functions. Accordingly, in a first aspect the invention features a process for preparing a molded article that includes bringing a moldable material and the surface of an open molding tool into line contact with each other to imprint a microfluid processing architecture onto the moldable material. The resulting molded article is then separated from the molding surface of the tool.
A xe2x80x9cmicrofluid processing architecturexe2x80x9d refers to one or more fluid-processing structures arranged in a pre-determined, self-contained pattern. Preferably, the architecture includes at least one structure having a dimension no greater than about 1000 micrometers. Moreover, fluid preferably enters and exits the architecture in the z-direction (i.e., the direction perpendicular to the plane of the architecture). For purposes of this invention, examples of suitable microfluid processing architectures include structures selected from the group consisting of microchannels, fluid reservoirs, sample handling regions, and combinations thereof.
An xe2x80x9copen molding toolxe2x80x9d is a molding tool that lacks a sealed cavity found in closed molds, e.g., of the type used in injection molding.
By xe2x80x9cline contactxe2x80x9d it is meant that the point at which the tool contacts the moldable material is defined by a line that moves relative to both the tool and the moldable material.
In one embodiment, the moldable material is an embossable polymeric substrate. The microfluid processing architecture pattern is embossed onto the surface of the polymeric substrate to create the molded article.
In another embodiment, the moldable material is a flowable resin composition. One example of such a composition is a curable resin composition, in which case the process includes exposing the composition to thermal or actinic radiation prior to separating the molded article from the molding surface to cure the composition. As used herein, xe2x80x9ccurexe2x80x9d and xe2x80x9ccurable resin compositionxe2x80x9d include crosslinking an already-polymerized resin, as well as polymerizing a monomeric or oligomeric composition, the product of which is not necessarily a crosslinked thermoset resin. An example of a preferred curable resin composition is a photopolymerizable composition which is cured by exposing the composition to actinic radiation while in contact with the molding surface.
Another example of a flowable resin composition is a molten thermoplastic composition which is cooled while in contact with the molding surface to solidify it.
There are two preferred molding processes in the case where the moldable material is a flowable resin composition. According to one preferred process, the flowable resin composition is introduced onto a major surface of a polymeric substrate, and the substrate and molding tool are moved relative to each other to bring the tool and flowable resin composition into line contact with each other. The net result is a two-layer structure in which a microfluid processing architecture-bearing layer is integrally bonded to the polymeric substrate.
A second preferred molding process where the moldable material is a flowable resin composition involves introducing the flowable resin composition onto the molding surface of the molding tool. A separate polymeric substrate may be combined with the flowable resin composition to create a two-layer structure in which a microfluid processing architecture-bearing substrate is integrally bonded to the polymeric substrate.
A substrate may be bonded to the molded article to form a cover layer overlying the microfluid processing architecture. Preferably, the substrate is a polymeric substrate. The molded article may also be provided with one or more microelectronic elements, microoptical elements, and/or micromechanical elements. These microelements may be incorporated in a variety of ways, illustrating the flexibility of the overall process. For example, where the moldable material is an embossable polymeric substrate, that substrate may include the microelements. Where the moldable material is a flowable resin composition and the process involves combining the resin composition with a polymeric substrate during molding, that polymeric substrate may include the microelements. It is also possible to include the microelements in the cover layer. The microelements may also be provided in the form of a separate substrate (preferably a polymeric substrate) that is bonded to the molded article.
The process is preferably designed to operate as a continuous process. Accordingly, moldable material is continuously introduced into a molding zone defined by the molding tool, and the molding tool is continuously brought into line contact with the moldable material to create a plurality of microfluid processing architectures. Preferably, the continuous process yields the article in the form of a roll that includes a plurality of microfluid processing architectures. The roll can be used as is or can be divided subsequently into multiple individual devices. Additional polymeric substrates can be continuously bonded to the article. Examples include cover layers and layers bearing microelectronic, microoptical, and/or micromechanical elements.
In a second aspect, the invention features an article that includes (A) a first non-elastic, polymeric substrate having a first major surface that includes a microfluid processing architecture (as defined above), and a second major surface; and (B) a second polymeric substrate that is integrally bonded to the second major surface of the first substrate. The second substrate is capable of forming a free-standing substrate in the absence of the first substrate. It provides mechanical support for the first substrate and also provides a means for incorporating additional features into the article such as microelectronic, microoptical, and/or micromechanical elements, thereby providing design flexibility.
A xe2x80x9cnon-elasticxe2x80x9d material is a material having insufficient elasticity in the zdirection (i.e., the direction normal to the plane of the substrate) to act as a pump or valve when subjected to a cyclically varying force in the z-direction.
xe2x80x9cIntegrally bondedxe2x80x9d means that the two substrates are bonded directly to each other, as opposed to being bonded through an intermediate material such as an adhesive.
The article preferably includes a cover layer overlying the microfluid processing architecture. The cover layer, which may be bonded to the first surface of the first substrate, preferably is a polymeric layer.
The article preferably includes one or more microelectronic, microoptical, and/or micromechanical elements. The microelements may be included in the first substrate, the second substrate, a polymeric cover layer, or a combination thereof.
In a third aspect, the invention features an article in the form of a roll that includes a first polymeric substrate having a first major surface that includes a plurality of discrete microfluid processing architectures (as defined above), and a second major surface. The article preferably includes a second polymeric substrate integrally bonded (as defined above) to the second major surface of the first substrate. The second substrate is capable of forming a free-standing substrate in the absence of the first substrate.
The article preferably includes a polymeric cover layer bonded to the first major surface of the first substrate.
The article preferably includes one or more microelectronic, microoptical, and/or micromechanical elements. The microelements may be included in the first substrate, the second substrate, a polymeric cover layer, or a combination thereof.
In a fourth aspect, the invention features an article that includes (A) a first polymeric substrate having a first major surface that includes a microfluid processing architecture (as defined above), and a second major surface; and (B) a second polymeric substrate. The second substrate has a first major surface that is integrally bonded (as defined above) to the second major surface of the first substrate, and a second major surface that includes one or more microelectronic elements and a via extending between the first and second major surfaces of the second substrate. The second substrate is capable of forming a free-standing substrate in the absence of the first substrate.
In a fifth aspect, the invention features an article that includes a first polymeric substrate having a first major surface that includes a microfluid processing architecture (as defined above), and a second major surface that includes one or more microelectronic elements and a via extending between the first and second major surfaces of the substrate.
In a sixth aspect, the invention features an article that includes (A) a first polymeric substrate having a first major surface that includes a microfluid processing architecture (as defined above), and a second major surface; and (B) a polymeric cover layer. The cover layer includes a first major surface overlying the first major surface of the substrate, and a second major surface that includes one or more microelectronic elements and a via extending between the first and second major surfaces of the cover layer.
In a seventh aspect, the invention features a method for processing a microfluid sample that includes (a) providing an article in the form of a roll comprising a first polymeric substrate having a first major surface that includes a plurality of discrete microfluid processing architectures, and a second major surface; (b) introducing a microfluid sample into one of the microfluid processing architectures; and (c) processing the sample (e.g., by analyzing the sample).
The invention provides polymeric articles useful for processing (e.g., analyzing) microfluid samples that can be continuously produced on a commercial scale in the convenient form of a roll good which can be readily stored and handled. The roll good can be used directly for processing a fluid sample, e.g., in a reel-to-reel continuous process involving injecting a different fluid into each microfluid processing architecture and then performing multiple operations. Alternatively, the roll good may be separated into a plurality of discrete devices following manufacture.
The manufacturing process offers significant design flexibility, enabling a number of processing steps to be performed in-line. For example, microelectronic, microoptical, and/or micromechanical elements can be readily incorporated into the article during manufacture in a variety of different ways, including as part of the substrate bearing the microfluid processing architecture, as part of a cover layer, or as part of a second polymeric substrate integrally bonded to the substrate. Various designs incorporating these microelements are also possible. Multilayer articles are readily prepared as well.
The molding process is sufficiently versatile to allow formation of a number of different microfluid processing architecture designs. Accordingly, articles can be manufactured to perform numerous functions, including, for example, capillary array electrophoresis, kinetic inhibition assays, competition immunoassays, enzyme assays, nucleic acid hybridization assays, cell sorting, combinatorial chemistry, and electrochromatography.
The molding process enables the preparation of microfluid processing architectures having high aspect ratio and variable aspect ratio features. This, in turn, provides structures exhibiting improved speed and resolution. For example, the depth of a microchannel can be varied while maintaining a constant microchannel width. Such microchannels can be used to construct vertically tapered inlet and outlet diffusers for a piezoelectric valve-less diffuser micropump, or used to provide electrokinetic zone control or electrokinetic focusing. Similarly, the width of a high aspect ratio microchannel can be tapered at constant depth. The resulting structure is also useful for providing electrokinetic zone control.
It is also possible to taper both the depth and width of the microchannels to provide a constant cross-sectional area or, alternatively, a constant cross-sectional perimeter. As a consequence of the constant cross-sectional area or perimeter, the resulting structure enables achievement of a constant voltage gradient throughout the length of the channel for predominantly electrophoretic flow or electroosmotic flow, thereby providing optical confinement for single molecule detection without loss of resolving power. This structure is also so useful for providing a transition between low aspect ratio and high aspect ratio structures (e.g., high aspect ratio injection tees, low aspect ratio probe capture zones, microwell reactors, or piezoelectric drive elements) without loss of electrokinetic resolving power.
It is also possible to prepare two intersecting microchannels having different depths. This feature, in turn, may be exploited to create a microfluidic switch in a hydrophobic substrate. Because of the depth difference, fluid in one arm of the relatively shallow microchannel will not cross the intersection unless a buffer is introduced into the relatively deeper microchannel to bridge the intersection. The variable depth feature is also useful for preparing post arrays for corralling probe capture beads in an immunoassay or nucleic acid assay, while simultaneously permitting the reporter reagent and fluid sample to flow freely.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.